JP6807054B2 - 環状アミン誘導体及びその医薬用途 - Google Patents
環状アミン誘導体及びその医薬用途 Download PDFInfo
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- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Description
カップリング反応に用いるハロゲン化アリール誘導体(III)の量は、ボロン酸誘導体(II)に対して0.5〜10当量が好ましく、0.7〜3当量がより好ましい。
縮合反応に用いるピペコリン酸誘導体(V)の量は、ビフェニルアミン誘導体(IV)に対して0.1〜10当量が好ましく、0.5〜3当量がより好ましい。
脱保護反応に用いる酸としては、例えば、塩酸、トリフルオロ酢酸又はフッ化水素酸が挙げられるが、塩酸又はトリフルオロ酢酸が好ましい。
縮合反応に用いる有機酸無水物誘導体(VIII)、有機酸エステル誘導体(IX)、有機酸クロリド誘導体(X)、有機酸誘導体(XI)又はイソシアン酸トリメチルシリルの量は、ピペコリン酸アミド誘導体(VII)に対して1〜200当量が好ましく、1〜80当量がより好ましい。
1H−NMR(400MHz,CDCl3)δ:3.79(s,2H),6.62(dd,J=8.3,2.3Hz,1H),6.80(d,J=2.3Hz,1H),7.05(d,J=8.3Hz,1H),7.30−7.41(m,4H).
ESI−MS:m/z=288(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.43−1.51(m,2H),1.53(s,9H),1.60−1.75(m,3H),2.35(d,J=12.7Hz,1H),2.80−2.89(m,1H),4.03−4.13(m,1H),4.86−4.89(m,1H),7.22(d,J=8.3Hz,1H),7.29−7.45(m,6H),7.80(br,1H).
ESI−MS:m/z=499(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.53(ddd,J=36.8,17.9,8.8Hz,4H),1.78−1.86(m,1H),2.00−2.07(m,1H),2.74−2.82(m,1H),3.03−3.10(m,1H),3.38(dd,J=9.6,3.5Hz,1H),7.23(d,J=8.3Hz,1H),7.31−7.37(m,3H),7.40−7.45(m,1H),7.53(dd,J=8.3,2.0Hz,1H),7.82(d,J=2.2Hz,1H),9.02(br,1H).
ESI−MS:m/z=399(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.46−1.63(m,1H),1.67(d,J=7.8Hz,1H),1.89−2.02(m,2H),2.22(s,3H),2.29(d,J=12.9Hz,1H),3.22(t,J=13.2Hz,1H),3.78(d,J=12.7Hz,1H),5.29(d,J=5.1Hz,1H),7.20(d,J=8.3Hz,1H),7.29−7.37(m,3H),7.40−7.44(m,2H),7.80(br,1H),8.65(br,1H).
ESI−MS:m/z=441(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.56−1.86(m,4H),1.98(dt,J=11.2,4.6Hz,1H),2.36(d,J=14.1Hz,1H),3.37(td,J=13.4,2.6Hz,1H),4.01(d,J=13.9Hz,1H),5.18(d,J=5.4Hz,1H),7.21(d,J=8.3Hz,1H),7.30−7.46(m,5H),7.79(br,1H),7.89(br,1H).
ESI−MS:m/z=495(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.22(t,J=7.3Hz,3H),1.55(br,2H),1.76(br,2H),1.97(t,J=13.2Hz,1H),2.30(d,J=12.7Hz,1H),2.48(dq,J=6.6,2.0Hz,2H),3.12(td,J=13.2,2.8Hz,1H),3.83(d,J=13.2Hz,1H),5.29(d,J=5.4Hz,1H),7.20(d,J=8.3Hz,1H),7.29−7.36(m,4H),7.39−7.45(m,1H),7.84(br,1H),8.56(br,1H).
ESI−MS:m/z=455(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.58−2.00(m,5H),2.33(d,J=14.4Hz,0.8H),2.48(d,J=12.7Hz,0.2H),2.63(t,J=12.7Hz,0.2H),3.14(t,J=13.0Hz,0.8H),3.48(s,2.4H),3.51(s,0.6H),3.82(d,J=12.7Hz,0.8H),4.12(d,J=11.7Hz,0.2H),4.18(d,J=13.9Hz,0.8H),4.26(d,J=13.9Hz,0.8H),4.34(d,J=11.7Hz,0.2H),4.52−4.60(m,0.2H),4.64−4.68(m,0.2H),5.23(d,J=6.1Hz,0.8H),7.20(d,J=8.3Hz,1H),7.28−7.45(m,5H),7.65−7.90(m,1H),8.46(br,0.8H),8.57(br,0.2H).
ESI−MS:m/z=471(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.48−1.55(m,1H),1.63−1.71(m,1H),1.75−1.85(m,2H),1.91−2.02(m,1H),2.32(d,J=13.4Hz,1H),3.17−3.25(m,1H),3.43−3.53(m,2H),4.28−4.32(m,2H),5.26(d,J=5.6Hz,1H),7.22(d,J=8.3Hz,1H),7.30−7.45(m,5H),7.77(br,1H),8.14(br,1H).
ESI−MS:m/z=457(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.40−2.20(m,6H),2.34(s,3H),2.47−2.50(m,3.4H),2.56−2.64(m,0.4H),2.92(d,J=12.6Hz,0.6H),3.06−3.14(m,0.4H),3.24(s,0.6H),3.67(d,J=12.6Hz,0.6H),4.03−4.07(m,0.4H),4.54−4.62(m,1.2H),5.24−5.27(m,0.4H),7.19−7.23(m,1H),7.30−7.46(m,5H),7.73−7.75(m,1H),8.53(br,0.4H),10.69(br,0.6H).
ESI−MS:m/z=484(M+H)+.
1H−NMR(400MHz,DMSO−D6)δ:1.40−1.80(m,5.0H),2.21−2.24(m,0.7H),2.29−2.34(m,0.3H),2.65−2.68(m,0.3H),3.46−3.55(m,0.7H),3.82−3.88(m,0.7H),4.28−4.34(m,0.3H),4.79−4.81(m,0.3H),5.07−5.10(m,0.7H),6.73(t,J=52.6Hz,0.3H),6.83(t,J=52.7Hz,0.7H),7.32(d,J=8.3Hz,1H),7.39−7.43(m,1H),7.45−7.51(m,2H),7.53−7.60(m,2H),7.90−7.93(m,1H),10.19(br,0.3H),10.25(br,0.7H).
ESI−MS:m/z=477(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.55−1.71(m,2H),1.76−1.84(m,2H),1.94−2.03(m,1H),2.32(d,J=14.5Hz,1H),3.29(td,J=13.1,2.7Hz,1H),3.67(d,J=12.7Hz,1H),4.68−4.76(m,2H),5.22(d,J=5.4Hz,1H),7.21−7.45(m,6H),7.81(br,1H),8.26(s,1H).
ESI−MS:m/z=523(M−H)−.
1H−NMR(400MHz,CDCl3)δ:1.46(s,9H),1.45−1.90(m,5H),2.38(d,J=13.2Hz,1H),3.21(t,J=12.1Hz,1H),3.75(d,J=13.9Hz,1H),3.95(dd,J=16.7,5.0Hz,1H),4.09−4.15(m,1H),5.32(d,J=4.9Hz,1H),5.42(br,1H),7.21(d,J=8.3Hz,1H),7.29−7.36(m,3H),7.40−7.45(m,1H),7.52(br,1H),7.80(br,1H),8.31(br,1H).
ESI−MS:m/z=556(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.45−1.63(m,2H),1.70−1.81(m,2H),1.89−1.99(m,1H),2.31(d,J=14.0Hz,1H),3.16(td,J=14.0,2.3Hz,1H),3.60(d,J=1.0Hz,2H),3.68(d,J=14.0Hz,1H),5.27(d,J=5.4Hz,1H),7.21(d,J=8.3Hz,1H),7.30−7.45(m,5H),7.77(br,1H),8.39(br,1H).
ESI−MS:m/z=456(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.57(s,9H),1.38−1.80(m,5H),2.46−2.53(m,1H),3.05(s,3H),3.15−3.22(m,1H),3.66(d,J=15.7Hz,1H),3.77−3.84(m,1H),4.41(d,J=15.7Hz,1H),5.41−5.44(m,1H),7.19(d,J=8.3Hz,1H),7.28−7.44(m,4H),7.70(br,1H),7.88(br,1H),8.61(br,1H).
ESI−MS:m/z=571(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.50−1.90(m,5H),2.09(s,3H),2.37(d,J=14.4Hz,1H),3.25(td,J=13.0,2.4Hz,1H),3.75(d,J=12.4Hz,1H),4.11(dd,J=17.2,4.0Hz,1H),4.21(dd,J=17.2,4.0Hz,1H),5.29(d,J=5.1Hz,1H),6.53(br,1H),7.21(d,J=8.5Hz,1H),7.29−7.37(m,3H),7.40−7.48(m,2H),7.80(br,1H),8.26(br,1H).
ESI−MS:m/z=498(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.52−1.95(m,5H),2.32(d,J=14.1Hz,1H),3.02(s,3H),3.33(t,J=12.8Hz,1H),3.64(d,J=13.0Hz,1H),4.08(d,J=4.6Hz,2H),5.25(d,J=4.6Hz,1H),5.48(br,1H),7.22(d,J=8.3Hz,1H),7.29−7.45(m,5H),7.81(br,1H),8.09(br,1H).
ESI−MS:m/z=534(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.26−1.76(m,5H),1.90−2.06(m,1H),2.28−2.42(m,1H),2.50(s,2.4H),2.60−2.63(m,0.8H),3.15(t,J=12.2Hz,0.8H),3.43(d,J=12.7Hz,0.2H),3.52(s,1.6H),3.70−3.76(m,1H),4.58−4.63(m,0.4H),5.28(d,J=4.9Hz,0.8H),7.19−7.23(m,1H),7.30−7.45(m,5H),7.75−7.77(m,1H),8.44(s,0.8H),10.49(s,0.2H).
ESI−MS:m/z=470(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.48−1.76(m,5H),2.20(s,3H),2.50−2.65(m,1H),3.24(s,2.1H),3.30(s,0.9H),3.20−3.31(m,1H),3.34(d,J=15.0Hz,0.3H),3.63(d,J=15.0Hz,0.7H),3.83−3.89(m,0.7H),4.60(d,J=15.0Hz,0.7H),4.64−4.70(m,0.6H),4.78(d,J=15.0Hz,0.3H),5.41(d,J=4.5Hz,0.7H),7.20−7.22(m,1H),7.30−7.35(m,3H),7.39−7.44(m,1H),7.60−7.75(m,0.7H),7.77(dd,J=8.4,2.0Hz,0.3H),7.98−8.07(m,0.7H),8.14(d,J=1.8Hz,0.3H),8.64(br,0.7H),9.63(br,0.3H).
ESI−MS:m/z=512(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.52−1.89(m,5H),2.35−2.38(m,1H),3.03−3.07(m,6H),3.20−3.31(m,1H),3.67−3.76(m,1H),4.16−4.27(m,2H),5.25−5.26(m,1H),7.21−7.23(m,1H),7.30−7.45(m,5H),7.83(s,1H),8.22(br,1H).
ESI−MS:m/z=548(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.47(t,J=7.4Hz,3H),1.58−1.68(m,2H),1.69−1.84(m,3H),2.59(d,J=12.4Hz,1H),3.06−3.21(m,4H),3.88(d,J=12.0Hz,1H),4.56(d,J=8.3Hz,1H),7.24(d,J=8.3Hz,1H),7.31−7.38(m,3H),7.40−7.50(m,2H),7.85(s,1H),8.53(br,1H).
ESI−MS:m/z=491(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.47−1.61(m,1H),1.62−1.81(m,4H),2.45(d,J=10.4Hz,1H),3.04(s,3H),3.23(td,J=13.3,2.4Hz,1H),3.93(t,J=7.0Hz,1H),4.64(br,1H),7.25(d,J=8.5Hz,1H),7.30−7.38(m,3H),7.43(dt,J=10.8,3.7Hz,2H),7.84(d,J=2.2Hz,1H),8.29(br,1H).
ESI−MS:m/z=477(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.42−1.64(m,2H),1.82(d,J=10.0Hz,2H),1.95(dt,J=8.8,4.3Hz,1H),2.35(d,J=13.9Hz,1H),3.29(td,J=13.2,2.8Hz,1H),3.63(d,J=9.5Hz,1H),5.12(d,J=5.6Hz,1H),7.21(d,J=8.3Hz,1H),7.28−7.45(m,5H),7.80(br,1H),8.21(d,J=9.2Hz,1H),8.32(br,1H).
ESI−MS:m/z=427(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.50−1.68(m,2H),1.73(br,2H),1.81−1.92(m,1H),2.30(d,J=12.9Hz,1H),3.21(dt,J=12.8,2.6Hz,1H),3.52(d,J=13.2Hz,1H),4.81(br,2H),5.03(d,J=4.6Hz,1H),7.20(d,J=8.3Hz,1H),7.29−7.37(m,3H),7.42(dt,J=10.8,3.8Hz,2H),7.81(br,1H),8.95(br,1H).
ESI−MS:m/z=442(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.48−1.78(m,4H),1.92−2.05(m,1H),2.27−2.35(m,1H),2.94(s,6H),2.87−2.99(m,1H),3.40−3.46(m,1H),4.47−4.51(m,1H),7.20(d,J=8.6Hz,1H),7.30−8.00(m,6H),10.60(br,1H).
ESI−MS:m/z=470(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.46−1.78(m,5H),2.30−2.41(m,1H),2.92(t,J=12.1Hz,1H),3.81(s,3H),4.05−4.20(br,1H),4.93(d,J=4.6Hz,1H),7.23(d,J=8.5Hz,1H),7.31−7.45(m,5H),7.74−7.86(m,1H),8.21(br,1H).
ESI−MS:m/z=457(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.43−1.51(m,2H),1.53(s,9H),1.60−1.75(m,3H),2.35(d,J=12.7Hz,1H),2.80−2.89(m,1H),4.03−4.13(m,1H),4.86−4.89(m,1H),7.22(d,J=8.3Hz,1H),7.29−7.45(m,6H),7.80(br,1H).
ESI−MS:m/z=499(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.53(ddd,J=36.8,17.9,8.8Hz,4H),1.78−1.86(m,1H),2.00−2.07(m,1H),2.74−2.82(m,1H),3.03−3.10(m,1H),3.38(dd,J=9.6,3.5Hz,1H),7.23(d,J=8.3Hz,1H),7.31−7.37(m,3H),7.40−7.45(m,1H),7.53(dd,J=8.3,2.0Hz,1H),7.82(d,J=2.2Hz,1H),9.02(br,1H).
ESI−MS:m/z=399(M+H)+.
測定機器;株式会社島津製作所 高速液体クロマトグラフ LC−2010CHT
カラム;ダイセル化学工業株式会社 CHIRALCEL OD−RH 0.46cmφ×15cm 粒子径 5μm
カラム温度;40℃
移動相;(A液)20mM リン酸二水素カリウム水溶液、(B液)アセトニトリル
移動相の組成;A液:B液=60:40〜50:50(0〜40分、リニアグラジエント)
A液:B液=50:50〜60:40(40〜41分、リニアグラジエント)
A液:B液=60:40(41分〜50分)
流速;0.5mL/分
検出;UV(210nm)
1H−NMR(400MHz,CDCl3)δ:1.46−1.63(m,1H),1.67(d,J=7.8Hz,1H),1.89−2.02(m,2H),2.22(s,3H),2.29(d,J=12.9Hz,1H),3.22(t,J=13.2Hz,1H),3.78(d,J=12.7Hz,1H),5.29(d,J=5.1Hz,1H),7.20(d,J=8.3Hz,1H),7.29−7.37(m,3H),7.40−7.44(m,2H),7.80(br,1H),8.65(br,1H).
ESI−MS:m/z=441(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.47−1.61(m,1H),1.62−1.81(m,4H),2.45(d,J=10.4Hz,1H),3.04(s,3H),3.23(td,J=13.3,2.4Hz,1H),3.93(t,J=7.0Hz,1H),4.64(br,1H),7.25(d,J=8.5Hz,1H),7.30−7.38(m,3H),7.43(dt,J=10.8,3.7Hz,2H),7.84(d,J=2.2Hz,1H),8.29(br,1H).
ESI−MS:m/z=477(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.50−1.68(m,2H),1.73(br,2H),1.81−1.92(m,1H),2.30(d,J=12.9Hz,1H),3.21(dt,J=12.8,2.6Hz,1H),3.52(d,J=13.2Hz,1H),4.81(br,2H),5.03(d,J=4.6Hz,1H),7.20(d,J=8.3Hz,1H),7.29−7.37(m,3H),7.42(dt,J=10.8,3.8Hz,2H),7.81(br,1H),8.95(br,1H).
ESI−MS:m/z=442(M+H)+.
測定機器;株式会社島津製作所 高速液体クロマトグラフ LC−2010CHT
カラム;ダイセル化学工業株式会社 CHIRALCEL OD−RH 0.46cmφ×15cm 粒子径 5μm
カラム温度;40℃
移動相;(A液)20mM リン酸二水素カリウム水溶液、(B液)アセトニトリル
移動相の組成;A液:B液=60:40〜50:50(0〜40分、リニアグラジエント)
A液:B液=50:50〜60:40(40〜41分、リニアグラジエント)
A液:B液=60:40(41〜50分)
流速;0.5mL/分
検出;UV(210nm)
1H−NMR(400MHz,CDCl3)δ:1.56−1.86(m,4H),1.98(dt,J=11.2,4.6Hz,1H),2.36(d,J=14.1Hz,1H),3.37(td,J=13.4,2.6Hz,1H),4.01(d,J=13.9Hz,1H),5.18(d,J=5.4Hz,1H),7.21(d,J=8.3Hz,1H),7.30−7.46(m,5H),7.79(br,1H),7.89(br,1H).
ESI−MS:m/z=495(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.33(d,J=6.6Hz,3H),1.82(d,J=11.7Hz,1H),1.87−1.95(m,1H),2.03−2.12(m,2H),2.47(td,J=11.8,5.1Hz,1H),3.19(d,J=5.1Hz,1H),3.35(dd,J=12.0,6.6Hz,1H),3.70(q,J=6.6Hz,1H),4.78(t,J=5.1Hz,1H),7.23−7.27(m,1H),7.31−7.35(m,2H),7.39−7.41(m,2H).
ESI−MS:m/z=232(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.48(s,9H),1.84−1.93(m,1H),1.95(d,J=12.0Hz,1H),2.03−2.06(m,1H),2.29−2.32(m,1H),3.18−3.21(m,1H),4.06(m,1H),4.70−4.85(m,1H),4.97(t,J=5.1Hz,1H).
ESI−MS:m/z=228(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.54(s,9H),1.66−1.69(m,1H),1.78−1.82(m,1H),1.93−2.00(m,1H),2.40(d,J=13.4Hz,1H),3.25(td,J=13.2,2.4Hz,1H),3.86−3.88(m,1H),4.12−4.14(m,1H),4.98−5.00(m,1H),5.20(br,1H),7.24(d,J=8.3Hz,1H),7.30−7.46(m,5H),7.75−7.78(m,1H),9.08(br,1H).
ESI−MS:m/z=515(M+H)+.
1H−NMR(DMSO−D6)δ:1.46−1.62(m,2H),1.91−1.94(m,1H),2.42−2.45(m,1H),3.01(t,J=12.2Hz,1H),3.28−3.32(m,1H),3.69−3.78(m,1H),4.00(d,J=12.0Hz,1H),5.28(d,J=4.9Hz,1H),7.38(d,J=8.3Hz,1H),7.42(dd,J=7.8,1.7Hz,1H),7.48−7.52(m,2H),7.56−7.64(m,2H),7.94(s,1H),8.93(br,1H),11.00(s,1H).
ESI−MS:m/z=415(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.48−1.56(m,1H),1.54(s,9H),1.59−1.86(m,2H),2.07−2.19(m,1H),2.65−2.71(m,1H),2.93(t,J=12.8Hz,1H),4.10−4.13(m,1H),5.04−5.06(m,1H),7.22(d,J=8.3Hz,1H),7.29−7.36(m,4H),7.41−7.45(m,1H),7.76(br,1H).
ESI−MS:m/z=517(M+H)+.
1H−NMR(DMSO−D6)δ:1.89−2.06(m,2H),2.24−2.33(m,1H),3.12−3.27(m,2H),4.18(d,J=12.4Hz,1H),5.16(d,J=47.1Hz,1H),7.38(d,J=8.5Hz,1H),7.42(dd,J=7.9,1.8Hz,1H),7.48−7.52(m,2H),7.56−7.61(m,2H),7.95(br,1H),9.12(br,1H),10.97(s,1H).
ESI−MS:m/z=417(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.28−1.37(m,2H),1.54(s,9H),1.67−1.74(m,1H),2.07−2.12(m,1H),2.61−2.63(m,1H),2.96−3.02(m,1H),4.12−4.14(m,1H),5.06(br,1H),5.43(br,1H),7.22(d,J=8.3Hz,1H),7.32−7.37(m,3H),7.41−7.45(m,2H),7.80(br,1H),8.06(s,1H).
ESI−MS:m/z=543(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.46−1.54(m,2H),1.54(s,9H),1.68−1.71(m,1H),1.94−1.97(m,1H),2.54−2.56(m,1H),2.86−2.93(m,1H),4.13−4.22(m,2H),5.04(br,1H),7.22(d,J=8.3Hz,1H),7.30−7.45(m,5H),7.78(br,1H),8.52(s,1H).
ESI−MS:m/z=515(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.56(s,9H),2.46−2.53(m,1H),2.61−2.73(m,2H),3.00(dd,J=16.5,3.3Hz,1H),3.66−3.73(m,1H),3.82(br,1H),5.05(s,1H),7.22(d,J=8.3Hz,1H),7.29−7.36(m,3H),7.41−7.45(m,2H),7.78(br,1H),9.14(br,1H).
ESI−MS:m/z=513(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.54(s,9H),1.86−2.15(m,3H),2.99−3.07(m,1H),3.21(td,J=13.3,2.7Hz,1H),4.22−4.25(m,1H),5.07(br,1H),7.24(d,J=8.5Hz,1H),7.30−7.37(m,3H),7.41−7.46(m,2H),7.76(s,1H),7.97(br,1H).
ESI−MS:m/z=535(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.68−1.76(m,1H),1.87−1.98(m,2H),2.24(s,3H),2.39(d,J=14.6Hz,1H),3.50−3.57(m,1H),3.61−3.66(m,1H),4.14−4.17(m,1H),5.42(d,J=6.8Hz,1H),5.52(d,J=6.8Hz,1H),7.23(d,J=8.5Hz,1H),7.31−7.37(m,3H),7.41−7.46(m,2H),7.77(br,1H),9.15(s,1H).
ESI−MS:m/z=457(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.69−1.85(m,2H),2.22−2.25(m,1H),2.25(s,3H),2.62−2.69(m,1H),3.21−3.28(m,1H),3.85(dd,J=13.4,2.9Hz,1H),5.24−5.43(m,1H),5.43(d,J=5.4Hz,1H),7.21(d,J=8.3Hz,1H),7.30−7.36(m,3H),7.41−7.45(m,2H),7.70−7.82(m,1H),8.72(s,1H).
ESI−MS:m/z=459(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.68−1.76(m,1H),1.85−1.88(m,1H),1.99(ddd,J=14.9,6.9,3.1Hz,1H),2.61(d,J=14.9Hz,1H),3.03(s,3H),3.55−3.62(m,1H),3.72(d,J=4.6Hz,1H),3.75−3.79(m,1H),4.22−4.24(m,1H),4.66(d,J=6.6Hz,1H),7.25−7.27(m,1H),7.31−7.37(m,3H),7.42−7.46(m,2H),7.81(d,J=2.0Hz,1H),8.58(s,1H).
ESI−MS:m/z=493(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.47−1.57(m,2H),1.81(d,J=3.6Hz,1H),2.04−2.09(m,1H),2.25(s,3H),2.50(ddt,J=13.1,5.0,1.8Hz,1H),3.22(td,J=13.4,2.6Hz,1H),3.85(d,J=13.4Hz,1H),4.40−4.48(m,1H),5.43(d,J=5.9Hz,1H),7.21(d,J=8.2Hz,1H),7.30−7.37(m,3H),7.41−7.45(m,2H),7.69−7.83(m,1H),8.65(s,1H).
ESI−MS:m/z=457(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.95−2.12(m,1H),2.15−2.32(m,2H),2.95−3.02(m,1H),3.10(s,3H),3.60(td,J=13.5,3.0Hz,1H),4.02−4.08(m,1H),4.89(d,J=7.2Hz,1H),7.26(d,J=8.2Hz,1H),7.30−7.37(m,3H),7.42−7.46(m,2H),7.76(s,1H),7.93(s,1H).
ESI−MS:m/z=513(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.48(s,9H),2.98(s,3H),3.00(s,3H),3.98(s,2H).
1H−NMR(400MHz,CDCl3)δ:2.99(s,3H),3.01(s,3H),4.14(s,2H).
ESI−MS:m/z=168(M+H)+.
測定機器;株式会社島津製作所 高速液体クロマトグラフ LC−2010CHT
カラム;ダイセル化学工業株式会社 CHIRALCEL OD−RH 0.46cmφ×15cm 粒子径 5μm
カラム温度;40℃
移動相;(A液)20mM リン酸二水素カリウム水溶液、(B液)アセトニトリル
移動相の組成;A液:B液=60:40〜50:50(0〜40分、リニアグラジエント)
A液:B液=50:50〜60:40(40〜41分、リニアグラジエント)
A液:B液=60:40(41〜50分)
流速;0.5mL/分
検出;UV(210nm)
1H−NMR(400MHz,CDCl3)δ:1.52−1.89(m,5H),2.35−2.38(m,1H),3.03−3.07(m,6H),3.20−3.31(m,1H),3.67−3.76(m,1H),4.16−4.27(m,2H),5.25−5.26(m,1H),7.21−7.23(m,1H),7.30−7.45(m,5H),7.83(s,1H),8.22(br,1H).
ESI−MS:m/z=548(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.39(s,9H),1.50−1.90(5H,m),2.35(d,J=13.7Hz,1H),2.55−2.75(m,2H),3.20(t,J=12.8Hz,1H),3.41−3.49(m,1H),3.50−3.60(m,1H),3.80(d,J=13.7Hz,1H)5.17(br,1H),5.33(d,J=4.9Hz,1H),7.20(d,J=8.3Hz,1H),7.29−7.60(m,5H),7.70−7.89(m,1H),8.65(br,1H).
ESI−MS:m/z=570(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.46−1.82(m,5H),2.43(d,J=13.1Hz,1H)2.56(dt,J=15.3,6.2Hz,1H),2.71−2.79(m,1H),3.09−3.21(m,3H),3.88(d,J=13.1Hz,1H),5.43(d,J=5.0Hz,1H),7.19(d,J=8.2Hz,1H),7.29−7.36(m,3H),7.40−7.85(m,3H),8.96(br,1H).
ESI−MS:m/z=470(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.46−1.94(m,5H),1.98(s,3H),2.34(d,J=13.3Hz,1H),2.60−2.73(m,2H),3.20(td,J=13.3,2.4Hz,1H),3.52−3.70(m,2H),3.79(d,J=13.3Hz,1H),5.30(d,J=4.5Hz,1H),6.23(br,1H),7.21(d,J=8.2Hz,1H),7.30−7.90(m,6H),8.51(br,1H).
ESI−MS:m/z=512(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.50−1.90(m,5H),2.33(d,J=13.5Hz,1H),2.75−2.80(m,2H)3.00(s,3H),3.22(t,J=13.5Hz,1H),3.45−3.51(m,2H),3.77(d,J=13.5Hz,1H),5.26−5.30(m,2H),7.22(d,J=8.3Hz,1H),7.30−7.44(m,5H),7.80(br,1H),8.22(br,1H).
ESI−MS:m/z=548(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.49−1.83(m,5H),2.27(s,6H),2.38−2.45(m,1H),2.56−2.61(m,1H),2.66−2.80(m,3H),3.12−3.20(m,1H),3.85−3.93(m,1H),5.42(d,J=5.4Hz,1H),7.21(d,J=8.3Hz,1H),7.27−7.45(m,6H),8.73(br,1H).
ESI−MS:m/z=498(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.35(s,9H),1.30−1.77(m5H,),2.37−2.80(m,3H),2.93(s,3H),3.18−3.30(m,2H)3.84(d,J=13.7Hz,1H),3.95−4.03(m,1H),5.38−5.42(m,1H),7.20(d,J=8.3Hz,1H),7.31−7.46(m,4H),7.66−7.72(m,1H),7.90−7.92(m,1H),9.10(br,1H).
ESI−MS:m/z=584(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.46−1.83(m,5H),2.47(s,3H),2.40−2.48(m,1H),2.75−2.83(m,1H),2.94−2.99(m,2H),3.16(td,J=13.1,2.6Hz,1H),3.88(d,J=13.1Hz,1H),5.41(d,J=5.4Hz,1H),7.21(d,J=8.3Hz,1H),7.30−7.81(m,6H),8.80(br,1H).
ESI−MS:m/z=484(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.48−1.77(m,5H),2.09(s,3H),2.45(d,J=13.7Hz,1H),2.59−2.79(m,2H),3.11(s,3H),3.20−3.29(m,2H),3.84(d,J=13.7Hz,1H),4.21−4.28(m,1H),5.35(d,J=5.1Hz,1H),7.20(d,J=8.3Hz,1H),7.31−7.36(m,3H),7.38−7.44(m,1H),7.70−7.80(m,1H),7.97−8.06(m,1H),9.09(br,1H).
ESI−MS:m/z=526(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.50−1.98(m,5H),2.35(d,J=13.5Hz,1H),2.76(dt,J=15.9,7.0Hz,1H)2.86(s,3H),2.83−2.89(m,1H),2.95(s,3H),3.20(td,J=13.5,2.7Hz,1H),3.50−3.57(m,2H),3.85(d,J=13.5Hz,1H),5.31(d,J=5.0Hz,1H),7.21(d,J=8.2Hz,1H),7.30−7.36(m,3H),7.40−7.52(m,2H),7.80−7.83(m,1H),8.42(br,1H).
ESI−MS:m/z=584(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.17(t,J=7.1Hz,3H),1.38−1.80(m,5H),1.90−2.00(m,1H),2.30−2.45(m,1H),2.55−2.90(m,2H),3.16(t,J=13.3Hz,1H),3.56(s,2H),3.70−3.76(m,1H),5.29(d,J=4.9Hz,1H),7.20−7.45(m,6H),7.70−7.90(m,1H),8.46(s,1H).
ESI−MS:m/z=484(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.25(t,J=7.1Hz,3H),1.50−1.90(m,5H),2.38(d,J=13.0Hz,1H),3.07(s,3H),3.25(t,J=13.0Hz,1H),3.43(q,J=7.1Hz,2H),3.76(d,J=13.0Hz,1H),4.14(d,J=17.0Hz,1H),4.30(d,J=17.0Hz,1H),5.27(d,J=4.6Hz,1H),7.21(d,J=8.3Hz,1H),7.29−7.36(m,3H),7.40−7.45(m,2H),7.83−7.85(m,1H),8.23(br,1H).
ESI−MS:m/z=584(M+Na)+.
1H−NMR(400MHz,CDCl3)δ:1.39(s,9H),1.50−1.90(5H,m),2.35(d,J=13.7Hz,1H),2.55−2.75(m,2H),3.20(t,J=12.8Hz,1H),3.41−3.49(m,1H),3.50−3.60(m,1H),3.80(d,J=13.7Hz,1H)5.17(br,1H),5.33(d,J=4.9Hz,1H),7.20(d,J=8.3Hz,1H),7.29−7.60(m,5H),7.70−7.89(m,1H),8.65(br,1H).
ESI−MS:m/z=570(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.46−1.82(m,5H),2.43(d,J=13.1Hz,1H)2.56(dt,J=15.3,6.2Hz,1H),2.71−2.79(m,1H),3.09−3.21(m,3H),3.88(d,J=13.1Hz,1H),5.43(d,J=5.0Hz,1H),7.19(d,J=8.2Hz,1H),7.29−7.36(m,3H),7.40−7.85(m,3H),8.96(br,1H).
ESI−MS:m/z=470(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.51−1.90(m,5H),2.18(s,3H),2.36(d,J=13.9Hz,1H),2.68−2.77(m,1H),2.80−2.99(m,3H),3.17(td,J=13.2,2.6Hz,1H),3.86(d,J=12.4Hz,1H),5.37(d,J=4.9Hz,1H),7.20(d,J=8.3Hz,1H),7.30−7.52(m,5H),7.66−7.90(m,1H),8.49(br,1H).
ESI−MS:m/z=501(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.50−1.82(m,5H),2.45−2.48(m,1H),2.79(td,J=11.0,5.9Hz,1H),3.06(s,3H),3.18−3.27(m,2H),3.40(dt,J=13.8,5.5Hz,1H),3.77−3.79(m,1H),3.93−3.96(m,1H),5.41(d,J=5.4Hz,1H),7.20(d,J=8.5Hz,1H),7.30−7.36(m,3H),7.40−7.44(m,1H),7.51−7.53(m,1H),7.86−7.89(m,1H),8.28(br,1H).
ESI−MS:m/z=533(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.35(s,9H),1.30−1.77(m5H,),2.37−2.80(m,3H),2.93(s,3H),3.18−3.30(m,2H)3.84(d,J=13.7Hz,1H),3.95−4.03(m,1H),5.38−5.42(m,1H),7.20(d,J=8.3Hz,1H),7.31−7.46(m,4H),7.66−7.72(m,1H),7.90−7.92(m,1H),9.10(br,1H).
ESI−MS:m/z=584(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.46−1.83(m,5H),2.47(s,3H),2.40−2.48(m,1H),2.75−2.83(m,1H),2.94−2.99(m,2H),3.16(td,J=13.1,2.6Hz,1H),3.88(d,J=13.1Hz,1H),5.41(d,J=5.4Hz,1H),7.21(d,J=8.3Hz,1H),7.30−7.81(m,6H),8.80(br,1H).
ESI−MS:m/z=484(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.50−1.92(m,4H),2.35(d,J=14.1Hz,1H),2.64−2.80(m,2H),3.06(t,J=6.3Hz,1H),3.19(td,J=13.2,2.4Hz,1H),3.83(d,J=14.1Hz,1H),3.98(q,J=5.4Hz,2H),5.34(d,J=5.4Hz,1H),7.21(d,J=8.0Hz,1H),7.30−7.44(m,6H),7.70−7.90(brm,1H),8.39(br,1H).
ESI−MS:m/z=471(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.50−1.80(m,5H),2.57−2.62(m,1H),3.16−3.25(m,1H),3.57(d,J=17.2Hz,1H),3.59−3.65(m,1H),3.84(s,3H),3.85(d,J=17.2Hz,2H),5.49(s,1H),7.22(d,J=8.2Hz,1H),7.30−7.37(m,3H),7.40−7.44(m,1H),7.92−7.95(m,1H),8.87(br,1H).
ESI−MS:m/z=499(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.52−1.60(m,5H),2.42−2.60(m,2H),2.62−2.70(m,1H),2.88−2.96(m,1H),2.99−3.08(m,1H),3.22(d,J=14.6Hz,1H),3.74(s,3H),3.97(d,J=14.6Hz,1H),5.46(d,J=5.4Hz,1H),7.21(d,J=8.3Hz,1H),7.28−7.44(m,6H),8.49(br,1H).
ESI−MS:m/z=513(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.46−1.87(m,5H),2.39(d,J=13.9Hz,1H),2.64(dt,J=15.0,5.7Hz,1H),2.85−2.92(m,1H),3.14(td,J=13.1,2.3Hz,1H),3.38(s,3H),3.67−3.78(m,1H),3.81−3.86(m,1H),3.92(d,J=13.9Hz,1H),5.40(d,J=4.9Hz,1H),7.21(d,J=8.3Hz,1H),7.29−7.80(m,6H),8.46(s,1H).
ESI−MS:m/z=483(M−H)−.
1H−NMR(400MHz,CDCl3)δ:1.62−1.71(m,2H),1.78−1.87(m,2H),1.99−2.11(m,1H),2.37(d,J=12.9Hz,1H),3.08−3.21(m,1H),3.96(s,3H),4.13−4.23(m,1H),5.18−5.20(m,1H),7.22(d,J=8.3Hz,1H),7.27−7.90(m,6H),7.70(s,1H),7.81(s,1H),9.18(br,1H).
ESI−MS:m/z=507(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.45−1.83(m,4H),2.15−2.32(m,2H),2.75−2.87(m,1H),3.79(s,3H),4.55−4.65(m,1H),5.31−5.37(m,1H),7.21(d,J=8.3Hz,1H),7.31−7.63(m,7H),7.75−7.90(m,1H),11.47(br,1H).
ESI−MS:m/z=507(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.45−1.90(m,4H),1.95−2.17(m,1H),2.33−2.43(m,1H),3.15−3.26(m,1H),4.09−4.21(m,1H),5.20−5.27(m,1H),7.22(d,J=8.5Hz,1H),7.28−7.52(m,5H),7.70−8.00(m,3H),9.16(br,1H),10.79(br,1H).
ESI−MS:m/z=493(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.24−1.76(m,5H),2.25−2.32(m,1H),2.99(s,3H),3.00(s,3H),3.25(td,J=13.0,3.2Hz,1H),3.58−3.64(m,1H),3.75(d,J=4.6Hz,3H),4.11(d,J=17.1Hz,1H),4.30(d,J=17.1Hz,1H),5.25(d,J=5.6Hz,1H).
ESI−MS:m/z=293(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.18−1.75(m,5H),2.30(d,J=13.1Hz,1H),2.98(s,3H),2.99(s,3H),3.24(t,J=12.0Hz,1H),3.63(d,J=13.1Hz,1H),4.13(d,J=17.2Hz,1H),4.27(d,J=17.2Hz,1H),5.24(d,J=4.1Hz,1H).
ESI−MS:m/z=279(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.49−1.85(m,5H),2.34(d,J=12.8Hz,1H),3.03(s,3H),3.03(s,3H),3.20(t,J=12.8Hz,1H),3.71(d,J=12.8Hz,1H),4.12(d,J=16.7Hz,1H),4.23(d,J=16.7Hz,1H),5.22(d,J=4.9Hz,1H),7.20−7.24(m,1H),7.50(dd,J=8.5,2.0Hz,1H),7.84(t,J=2.3Hz,1H),8.20(br,1H).
ESI−MS:m/z=467(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.20(d,J=6.0Hz,6H),1.50−1.88(m,5H),2.31−2.39(m,1H),3.05(s,3H),3.05(s,3H),3.21−3.28(m,1H),3.69−3.74(m,1H),4.19(d,J=16.8Hz,1H),4.25(d,J=16.8Hz,1H),4.41(t,J=6.0Hz,1H),5.23−5.26(m,1H),6.95−7.00(m,2H),7.17(dd,J=7.4,2.0Hz,1H),7.22−7.37(m,3H),7.76(d,J=2.0Hz,1H),8.11(s,1H).
ESI−MS:m/z=523(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.49−1.80(m,5H),2.67−2.74(m,1H),3.20−3.27(m,1H),3.54−3.62(m,1H),3.63(s,3H),3.73(d,J=15.9Hz,1H),4.05(d,J=15.9Hz,1H),5.59−5.63(m,1H),6.89−6.98(m,2H),7.20−7.29(m,1H),7.32−7.37(m,3H),7.39−7.45(m,1H),7.71−7.99(m,2H),10.64(br,1H).
ESI−MS:m/z=521(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.48−1.83(m,5H),2.31−2.39(m,1H),3.03(s,3H),3.03(s,3H),3.16−3.23(m,1H),3.68−3.75(m,1H),4.10(d,J=16.6Hz,1H),4.24(d,J=16.6Hz,1H),5.21−5.24(m,1H),7.06(dd,J=9.0,2.0Hz,1H),7.43(t,J=8.2Hz,1H),7.63(dd,J=10.5,2.4Hz,1H),8.24(br,1H).
ESI−MS:m/z=451(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.45−1.90(m,5H),2.33−2.41(m,1H),3.05(s,6H),3.20−3.29(m,1H),3.69−3.76(m,1H),4.17(d,J=16.8Hz,1H),4.25(d,J=16.8Hz,1H),5.23−5.27(m,1H),7.20−7.44(m,6H),7.62(dd,J=11.7,2.0Hz,1H),8.24(br,1H).
1H−NMR(400MHz,CDCl3)δ:1.44−2.05(m,5H),2.23−2.31(m,1H),3.37−3.47(m,1H),3.67−3.74(m,1H),4.86(d,J=16.6Hz,1H),4.91(d,J=16.6Hz,1H),5.16−5.22(m,1H),6.97(s,1H),7.13(s,1H),7.20(d,J=8.3Hz,1H),7.29−7.37(m,4H),7.40−7.45(m,1H),7.53(s,1H),7.70−7.87(m,1H),8.41(br,1H).
ESI−MS:m/z=507(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.59−2.02(m,5H),2.29−2.32(m,1H),3.49−3.57(m,1H),3.73−3.77(m,1H),5.18−5.19(m,1H),5.40(d,J=16.8Hz,1H),5.48(d,J=16.8Hz,1H),7.21−7.46(m,6H),7.81(br,1H),8.02(s,1H),8.86(s,1H).
ESI−MS:m/z=509(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.41−1.95(m,5H),2.33−2.38(m,1H),3.08−3.16(m,1H),3.85−3.97(m,3H),5.34−5.36(m,1H),6.22−6.23(m,1H),6.35−6.37(m,1H),7.19−7.44(m,8H),8.33(br,1H).
ESI−MS:m/z=505(M−H)−.
1H−NMR(400MHz,CDCl3)δ:1.46−1.66(m,2H),1.74−1.79(m,3H),2.08(s,3H),2.27(s,3H),2.47−2.50(m,1H),3.11−3.19(m,1H),3.69−3.74(m,1H),4.83(d,J=15.2Hz,1H),4.96(d,J=15.2Hz,1H),5.35−5.36(m,1H),5.89(s,1H),7.21−7.45(m,7H),8.86(br,1H).
ESI−MS:m/z=535(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.47−1.96(m,5H),2.29(s,3H),2.33−2.39(m,1H),3.21−3.28(m,1H),3.82−3.87(m,1H),3.95(d,J=16.1Hz,1H),4.01(d,J=16.1Hz,1H),5.32−5.33(m,1H),6.08(s,1H),7.21−7.45(m,7H),8.27(br,1H).
ESI−MS:m/z=520(M−H)−.
測定機器;株式会社島津製作所 高速液体クロマトグラフ LC−2010CHT
カラム;ダイセル化学工業株式会社 CHIRALCEL OD−RH 0.46cmφ×15cm 粒子径 5μm
カラム温度;40℃
移動相;(A液)蒸留水、(B液)アセトニトリル
移動相の組成;A液:B液=60:40(0〜75分)。
流速;0.5mL/分
検出;UV(210nm)
1H−NMR(400MHz,CDCl3)δ:1.62−2.00(m,5H),2.27−2.31(m,1H),3.52−3.58(m,1H),3.73−3.76(m,1H),5.18−5.19(m,1H),5.40(d,J=16.5Hz,1H),5.48(d,J=16.5Hz,1H),7.21−7.45(m,6H),7.81(br,1H),8.15(s,1H),8.86(s,1H).
ESI−MS:m/z=509(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.43−1.97(m,5H),2.25−2.29(m,1H),3.04−3.19(m,2H),3.25(td,J=13.0,2.7Hz,1H)3.70−3.74(m,1H),4.79−4.92(m,2H),5.18−5.19(m,1H),7.22−7.44(m,6H),7.79(br,1H),8.13(br,1H),8.84(s,1H).
ESI−MS:m/z=521(M−H)−.
1H−NMR(400MHz,CDCl3)δ:1.37−1.99(m,5H),2.26−2.29(m,1H),2.87−2.91(m,2H),3.17(td,J=13.3,2.7Hz,1H)3.67−3.71(m,1H),4.34−4.47(m,2H),5.24−5.25(m,1H),6.99(s,1H),7.06(s,1H),7.21−7.45(m,6H),7.58(br,1H),7.71−7.82(m,1H),8.33(br,1H).
ESI−MS:m/z=521(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.37−1.89(m,5H),2.12(s,3H),2.35−2.38(m,1H),2.85−3.12(m,3H),3.67−3.70(m,1H),4.38−4.44(m,1H),4.51−4.58(m,1H),5.30−5.32(m,1H),5.96−5.97(m,1H),7.19−7.45(m,8H),8.59(br,1H).
ESI−MS:m/z=535(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.46−1.74(m,5H),2.52−2.55(m,1H),3.04−3.12(m,1H),3.65−3.69(m,1H),5.01(d,J=14.5Hz,1H),5.22(d,J=14.5Hz,1H),5.43−5.44(m,1H),6.39(dd,J=2.3,2.0Hz,1H),7.24(d,J=8.2Hz,1H),7.32−7.37(m,3H),7.41−7.45(m,1H),7.52−7.61(m,1H),7.53(d,J=2.3Hz,1H),7.58(d,J=2.0Hz,1H),7.80−7.87(brm,1H),9.02(s,1H).
ESI−MS:m/z=507(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.55−1.90(m,5H),2.29−2.32(m,1H),3.57−3.71(m,2H),4.93(d,J=16.8Hz,1H),5.02(d,J=16.8Hz,1H),5.22−5.23(m,1H),7.19(d,J=8.2Hz,1H),7.28−7.37(m,4H),7.40−7.45(m,1H),7.81(s,1H),8.21(s,2H),8.84(s,1H).
ESI−MS:m/z=508(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.54−1.70(m,2H),1.77−1.90(m,3H),2.38−2.41(m,1H),3.31−3.39(m,1H),3.74−3.78(m,1H),5.13(d,J=15.4Hz,1H),5.22(d,J=15.4Hz,1H),5.29(d,J=5.0Hz,1H),7.23(d,J=8.2Hz,1H),7.30−7.37(m,4H),7.41−7.45(m,1H),7.79(brs,1H),8.02(s,1H),8.26(s,1H),8.39(s,1H).
ESI−MS:m/z=508(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.51−1.70(m,2H),1.76−1.88(m,3H),2.39−2.42(m,1H),3.32−3.39(m,1H),3.74−3.78(m,1H),5.30−5.31(m,1H),5.34(d,J=15.4Hz,1H),5.41(d,J=15.4Hz,1H),7.23(d,J=8.6Hz,1H),7.30−7.37(m,3H),7.41−7.45(m,1H),7.52(brs,1H),7.76(d,J=0.9Hz,1H),7.82(d,J=0.9Hz,1H),7.91(brs,1H),8.43(s,1H).
ESI−MS:m/z=508(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.44−2.05(m,5H),2.23−2.31(m,1H),3.37−3.47(m,1H),3.67−3.74(m,1H),4.86(d,J=16.6Hz,1H),4.91(d,J=16.6Hz,1H),5.16−5.22(m,1H),6.97(s,1H),7.13(s,1H),7.20(d,J=8.3Hz,1H),7.29−7.37(m,4H),7.40−7.45(m,1H),7.53(s,1H),7.70−7.87(m,1H),8.41(brs,1H).
ESI−MS:m/z=507(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.47−1.65(m,2H),1.68−1.77(m,3H),2.49−2.52(m,1H),2.98−3.06(m,1H),3.55−3.58(m,1H),5.33(d,J=15.0Hz,1H),5.42(d,J=5.0Hz,1H),5.57(d,J=15.0Hz,1H),7.24(d,J=8.2Hz,1H),7.32−7.37(m,3H),7.41−7.46(m,1H),7.42−7.88(brm,2H),7.73(s,2H),8.63(s,1H).
ESI−MS:m/z=530(M+Na)+.
1H−NMR(400MHz,CDCl3)δ:1.29(t,J=7.2Hz,3H),2.55(s,3H),3.92(s,2H),4.23(q,J=7.2Hz,2H).
ESI−MS:m/z=171(M+H)+.
1H−NMR(400MHz,DMSO−D6)δ:2.41(s,3H),3.38(s,2H).
ESI−MS:m/z=143(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.50−1.66(m,3H),1.74−1.77(m,2H),2.57(s,3H),2.62−2.65(m,1H),3.27−3.34(m,1H),3.61−3.64(m,1H),3.94(d,J=17.4Hz,1H),4.21(d,J=17.4Hz,1H),5.54−5.55(m,1H),7.25−7.27(m,1H),7.33−7.36(m,3H),7.40−7.44(m,1H),7.77(brs,1H),8.18(brs,1H),9.38(s,1H).
ESI−MS:m/z=545(M+Na)+.
1H−NMR(400MHz,CDCl3)δ:1.46−1.83(m,5H),2.26(s,0.6H),2.28(s,5.4H),2.40−2.44(m,1H),2.55−2.62(m,1H),2.65−2.81(m,3H),2.99−3.05(m,0.1H),3.13−3.20(m,0.9H),3.88−3.91(m,0.9H),4.69(d,J=5.0Hz,0.1H),4.73−4.76(m,0.1H),5.43(d,J=5.0Hz,0.9H),7.21(d,J=8.6Hz,1H),7.31−7.86(m,6H),8.76(br,0.9H),9.33(br,0.1H).
ESI−MS:m/z=498(M+H)+.
1H−NMR(400MHz,CDCl3)δ:1.44−1.79(m,4H),1.84−1.95(m,1H),1.96−2.13(m,2H),2.35(d,J=13.7Hz,1H),2.40−2.62(m,4H),2.63−2.70(m,0.1H),3.14−3.21(m,0.9H),3.68(s,2.7H),3.69(s,0.3H),3.84−3.88(m,0.9H),4.66−4.69(m,0.2H),5.34(d,J=5.0Hz,0.9H),7.20(d,J=8.2Hz,1H),7.29−7.94(m,6H),8.68(s,0.9H),8.90(s,0.1H).
1H−NMR(400MHz,CDCl3)δ:1.49−1.79(m,4H),1.84−1.94(m,1H),2.00−2.10(m,2H),2.32(d,J=13.6Hz,1H),2.44−2.63(m,4H),3.20(td,J=13.3,2.6Hz,1H),3.81−3.87(m,1H),5.30(d,J=4.5Hz,1H),7.20(d,J=8.6Hz,1H),7.29−7.36(m,3H),7.40−7.45(m,2H),7.75−7.88(m,1H),8.62(s,1H).
ESI−MS:m/z=535(M+Na)+.
RORγのリガンド結合ドメイン(以下、RORγ−LBD)とコアクチベーターとの結合に対する、環状アミン誘導体(I)又はその薬理学的に許容される塩の阻害作用を、時間分解蛍光エネルギー移動(TR−FRET)を利用したinvitrogen社のLanthaScreenTM TR−FRET Retinoid−Related Orphan Receptor (ROR) gamma Coactivator Assayキットを用いて評価した。
RORγ−コアクチベーター結合阻害率(%)=(1−((被験化合物添加時のFold change)−(バックグラウンドのFold change))/((コントロールのFold change)−(バックグラウンドのFold change)))×100・・・式1
マウス脾細胞を用いて、IL−23刺激によるIL−17産生に対する環状アミン誘導体(I)又はその薬理学的に許容される塩の抑制作用を、The Journal of Biological Chemistry、2003年、第278巻、3号、p.1910−1914に記載の方法を一部改変して評価した。
IL−17産生抑制率(%)=(1−((IL−23添加かつ被験化合物添加時のIL−17産生量)−(IL−23非添加かつ被験化合物非添加時のIL−17産生量))/((IL−23添加かつ被験化合物非添加時のIL−17産生量)−(IL−23非添加かつ被験化合物非添加時のIL−17産生量)))×100・・・式2
神経症状スコアの上昇を症状悪化の指標として、マウス実験的自己免疫性脳脊髄炎モデルにおける環状アミン誘導体(I)又はその薬理学的に許容される塩の作用を評価した。マウス実験的自己免疫性脳脊髄炎モデルは、Hindingerらの方法(Journal of Neuroscience Research、2006年、84巻、p.1225−1234)を一部改変して作製した。
耳介の厚みの増加を症状悪化の指標として、イミキモド誘発マウス乾癬モデルにおける環状アミン誘導体(I)又はその薬理学的に許容される塩の作用を評価した。イミキモド誘発マウス乾癬モデルは、Schaperらの方法(The Journal of Dermatological Science、2013年、第71巻、第1号、p.29−36)を一部改変して作製した。
耳介腫脹率の増加を症状悪化の指標として、DNFB誘発マウスアレルギー性皮膚炎モデルにおける環状アミン誘導体(I)又はその薬理学的に許容される塩の作用を評価した。DNFB誘発マウスアレルギー性皮膚炎モデルは、Curzytekらの方法(Pharmacological Reports、2013年、第65巻、p.1237−1246)を一部改変して作製した。
耳介腫脹率(%)=((惹起24時間後の右耳介の厚み)−(惹起前の右耳介の厚み))/惹起前の右耳介の厚み×100・・・式3
耳介の厚みの増加を症状悪化の指標として、オキサゾロン誘発マウスアトピー性皮膚炎モデルにおける環状アミン誘導体(I)又はその薬理学的に許容される塩の作用を評価した。オキサゾロン誘発マウスアトピー性皮膚炎モデルは、Nakajimaらの方法(Journal of Investigative Dermatology、2014年、第134巻、p.2122−2130)を一部改変して作製した。
Claims (11)
- 下記の一般式(I)で示される環状アミン誘導体又はその薬理学的に許容される塩。
- R1は、1〜3個の任意の水素原子がフッ素原子又は塩素原子で置換されていてもよい炭素数1〜3のアルキルオキシ基であり、
R2は、フッ素原子又は塩素原子であり、
R3は、水素原子、フッ素原子、塩素原子又は水酸基であり、
R4は、水素原子、フッ素原子又は塩素原子であり、
R5は、水素原子、−OR7、−SR7、−S(=O)2−R7、−C(=O)−OR7、−N(R7)R8、1〜3個の任意の水素原子がフッ素原子若しくは塩素原子で置換されていてもよい炭素数1〜3のアルキル基又は任意の水素原子がメチル基で置換されていてもよいヘテロアリール基であり、
R6は、炭素数1〜3のアルキル基であり、
R7は、水素原子又は1〜3個の任意の水素原子がフッ素原子若しくは塩素原子で置換されていてもよい炭素数1〜3のアルキル基である、請求項1記載の環状アミン誘導体又はその薬理学的に許容される塩。 - R1は、1〜3個の任意の水素原子がフッ素原子で置換されていてもよいメトキシ基であり、
R2は、フッ素原子又は塩素原子であり、
R3は、水素原子、フッ素原子又は水酸基であり、
R4は、水素原子又はフッ素原子であり、
nは、0〜4の整数であり、
R5は、水素原子、−OR7、−N(R7)R8、1〜3個の任意の水素原子がフッ素原子で置換されていてもよい炭素数1〜3のアルキル基又は任意の水素原子がメチル基で置換されていてもよい5員環ヘテロアリール基であり、
R6は、メチル基又はエチル基であり、
R7は、水素原子又は1〜3個の任意の水素原子がフッ素原子で置換されていてもよい炭素数1〜3のアルキル基であり、
R8は、水素原子、メチル基、炭素数2〜4のアシル基又は炭素数1〜3のアルキルスルホニル基である、請求項1記載の環状アミン誘導体又はその薬理学的に許容される塩。 - R1は、トリフルオロメトキシ基であり、
R2は、塩素原子であり、
R3は、水素原子であり、
R4は、水素原子であり、
Xは、−C(=O)−(CH2)n−R5であり、
nは、0〜3の整数であり、
R5は、メチル基、トリフルオロメチル基、−N(R7)R8又は任意の水素原子がメチル基で置換されていてもよい、イミダゾリル基、トリアゾリル基若しくはテトラゾリル基であり、
R7は、水素原子、メチル基又はエチル基であり、
R8は、水素原子、メチル基、アセチル基、プロピオニル基、メチルスルホニル基又はエチルスルホニル基である、請求項1記載の環状アミン誘導体又はその薬理学的に許容される塩。 - 請求項1〜4のいずれか一項記載の環状アミン誘導体又はその薬理学的に許容される塩を有効成分として含有する、医薬。
- 請求項1〜4のいずれか一項記載の環状アミン誘導体又はその薬理学的に許容される塩を有効成分として含有する、レチノイド関連オーファン受容体γアンタゴニスト。
- 請求項1〜4のいずれか一項記載の環状アミン誘導体又はその薬理学的に許容される塩を有効成分として含有する、自己免疫疾患の治療剤又は予防剤。
- 請求項1〜4のいずれか一項記載の環状アミン誘導体又はその薬理学的に許容される塩を有効成分として含有する、多発性硬化症又は乾癬の治療剤又は予防剤。
- 請求項1〜4のいずれか一項記載の環状アミン誘導体又はその薬理学的に許容される塩を有効成分として含有する、アレルギー性疾患の治療剤又は予防剤。
- 請求項1〜4のいずれか一項記載の環状アミン誘導体又はその薬理学的に許容される塩を有効成分として含有する、アレルギー性皮膚炎の治療剤又は予防剤。
- 請求項1〜4のいずれか一項記載の環状アミン誘導体又はその薬理学的に許容される塩を有効成分として含有する、接触性皮膚炎又はアトピー性皮膚炎の治療剤又は予防剤。
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TWI691486B (zh) | 2020-04-21 |
JPWO2017131156A1 (ja) | 2018-11-22 |
HUE050744T2 (hu) | 2021-01-28 |
RU2696862C1 (ru) | 2019-08-07 |
KR20180100573A (ko) | 2018-09-11 |
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